PROJECT ABSTRACT This application is for a Mentored Patient-Oriented Research Career Development Award entitled ?Metabolic Effects of Early Nutritional Support in Sepsis: A Translational Investigation.? I am a pulmonary and critical care physician at the University of Pittsburgh Medical Center who requires additional training to develop expertise as a translational researcher using metabolic assessment studies in animal models of sepsis to guide the development of interventions in patients with critical illness. The central objective of my research project is to determine how early caloric support impacts metabolism and inflammatory outcomes in the acute phase of sepsis. Preliminary data from our mouse models suggest that provision of dextrose via an intravenous route, even at low levels early in the course of sepsis, markedly impairs glucose tolerance and decreases insulin sensitivity and insulin secretion. We propose that this metabolic dysfunction is mediated through systemic cytokine release initiated by inflammasome activation of IL1-?. In contrast, provision of low-level dextrose by the enteral route during early sepsis, is associated with increased levels of circulating incretin hormones, decreased IL1-? and pro-inflammatory cytokines, and significant improvements in glucose metabolism. The aims of the study are (1) to determine the effects of early caloric support on inflammasome activation and metabolism in a mouse model of sepsis, (2) to explore the potentially protective role of enteral activation of the incretin hormone pathway on inflammation and glucose tolerance in the acute phase of murine sepsis, and (3) to translate findings on the beneficial role of early enteral dextrose in a pilot interventional trial in critically-ill patients with sepsis. These studies will provide insight into the optimal timing and route of early caloric support in the care of septic patients?an area of clinical practice lacking in fundamental biology and clear guidelines for physicians. The project will provide a unique translational training opportunity that combines exploration of the metabolic effects of early caloric support in complex animal models with a pilot interventional human study. The work will be conducted within the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Pittsburgh, which has an outstanding record of training physician-scientists and a highly developed infrastructure for the conduct of translational studies. I am supported by a committed mentoring partnership of a PhD, with expertise in murine models and metabolism, and an MD, with expertise in critical illness and patient-orientated research. I will complete my MPH training to gain formal exposure to clinical research practices and have assembled an Advisory Committee to provide advanced training exposure in the areas of inflammation, metabolism, and clinical research.